Metalloproteinases, including matrix metalloproteinase (MMP), (human fibroblast) collagenase, gelatinase and tumour necrosis factor (TNF), and their modes of action, and also inhibitors thereof and their clinical effects, are described in WO-A-9611209, the content of which is incorporated herein by reference.
Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF both in vitro and in vivo. See Gearing et al (1994), Nature 370:555-557; McGeehan et al (1994), Nature 370:558-561; GB-A-2268934; and WO-A-9320047. All of these reported inhibitors contain a hydroxamic acid zinc binding group, as do the imidazole-substituted compounds disclosed in WO-A-9523790. Other compounds that inhibit MMP and TNF are described in WO-A-9513289 and WO-A-9611209.
Compounds that inhibit collagenase, which possess structural portions akin to those of the instant invention, include those encompassed by U.S. Pat. No. 4,511,504 issued Apr. 16, 1985; and U.S. Pat. No. 4,568,666, issued Feb 4, 1986.
Compounds of related structure that are claimed to inhibit stromelysin (proteoglycanase) are encompassed by U.S. Pat. No. 4,771,037, issued Sep. 13, 1988.
Recent reports suggest that new enzymes of the MMP family also mediate the shedding of adhesion molecules such as the selecting, such as L-selectin. These soluble adhesion molecules are implicated in a number of diseases including cancer, autoimmunity and in the inflammatory response. It has been proposed that, once cleaved, the selectin bind to particular ligands and this accounts for their biological activity. Thus, drugs that interfere with or prevent binding of the ligands to the selectins will be useful medicaments for treating a variety of the diseases described above.